This Pilot and Feasibility Program (R-21) application represents a new research direction for the investigator, Dr. Mary Samuels, in the field of cognitive effects of mild (or "subclinical") thyroid disease in the adult human. 5% of the general population has subclinical thyroid disease, as defined by isolated TSH abnormalities, and 20% of older women have mild hypothyroidism (isolated TSH elevations). Therefore, the question of whether subclinical thyroid disease alters cognition has important public health implications. If subclinical thyroid disease were associated with cognitive deficits, this would be an important treatment indication. This is especially relevant to the older population, which has high rates of incipient dementia that could be worsened by the addition of cognitive deficits due to mild thyroid disease. [unreadable] [unreadable] In order to investigate this question, the investigator has designed a new model of experimentally-induced subclinical thyroid disease, and proposes a series of experiments to test and refine this model. Subjects who are currently taking L-thyroxine (L-T4) for chronic replacement therapy will be randomized to their usual doses of L-T4, vs. slightly lower doses (to induce mild subclinical hypothyroidism), or slightly higher doses (to induce mild subclinical hyperthyroidism). Treatment assignment is randomized, placebo-controlled, and double-blinded. Each treatment arm is designed to last 3 months. At the beginning and end of each arm, a battery of cognitive tests is administered. The specific cognitive outcome measures have been chosen to target cognitive domains most likely to be affected by mild thyroid disease. Throughout the studies, subjects are also monitored for safety, quality of life, mood, and other effects of altered thyroid function. The broad specific aims of this application are: 1) To develop and refine a model of experimentally-induced subclinical thyroid disease by testing dose increments of L-T4 in subjects receiving L-T4 replacement therapy; 2) To utilize the model to obtain pilot data on cognitive effects induced by subclinical hypothyroidism in younger and older human subjects; and 3) To utilize the model to obtain pilot data on cognitive deficits induced by subclinical hyperthyroidism in older subjects. Based on these pilot studies, it is the long-term goal of the investigator to investigate specific cognitive effects of altered thyroid status in the adult human. [unreadable] [unreadable]